Transdermal drug delivery system

ABSTRACT

In a transdermal drug delivery system, encapsulation material used to coat drug granules controls the release of an active ingredient. The active ingredient is released into a water retaining matrix, which acts as a reservoir, and transdermal drug penetration is driven by the resulting concentration gradient. The delivery system is enclosed in a patch comprising a composite shell, which acts as an occlusive covering when attached to skin, thus enhancing the hydration of the skin area and fostering absorption of the drug. Visible change indicators incorporated into the system provide indicators at significant &#34;landmarks&#34; in the lifetime of the patch. Microcapsules used for the indicator may be formulated so that the penetration of moisture effects a color change at a time when the active ingredient is almost exhausted. This feature alerts to the user to the need for application of a replacement patch.

FIELD OF INVENTION

This invention relates to a transdermal drug delivery system, and moreparticularly, to a drug delivery system in which drug granules areencapsulated within material which controls the release over time of anactive ingredient. In accordance with the invention, the activeingredient is released into a water retaining matrix.

BACKGROUND OF THE INVENTION

Devices and methods have been developed for the administration ofpharmaceuticals at desired sustained levels by absorption through theskin. Transdermal delivery systems are available, or have been proposed,for many pharmaceutical agents. Typically, devices used in suchtechniques (often referred to as "patches") are attached to the skin ofa patient, usually adhesively. The active agent is caused to diffusefrom the device through the skin for absorption into the bloodstream.Upon absorption into the bloodstream, the agent is carried throughoutthe body of the patient.

Numerous techniques have been proposed to control the rate of release ofpharmaceutical agents in transdermal delivery systems. For example, inU.S. Pat. Nos. 4,314,557 and 4,460,472, systems are disclosed whichcontrol the rate of release of an agent by the rate of which a drugsolute phase dissolves in a polymer matrix phase. In U.S. Pat. No.4,379,454, a drug and an absorption enhancer are said to be contained ina solid, semi-solid or gel matrix phase.

U.S. Pat. No. 4,409,206 describes a transdermal release system using askin-compatible polyacrylate, which swells with water and may contain ahydrophilic component to regulate the rate of release.

U.S. Pat. No. 4,624,665 suggests sealing the skin with an occlusivelayer, and transporting a desired dosage of an active agent across thelayer from a rate controlling system.

U.S. Pat. No. 4,645,502 discloses an encapsulated permeation enhancerand a dry active agent within an aqueous gelled reservoir.

U.S. Pat. No. 4,690,683 discloses an active pharmaceutical dispersed ina polymeric material to form, by cross-linking, a matrix. As analternative, a solution of the active pharmaceutical may be dispersed inthe matrix prior to cross-linking, in which case, the patent says,"micro reservoirs" of the drug are formed in the matrix. A suggestion isalso made in this patent of the possibility of incorporating a bufferingagent into the matrix.

U.S. Pat. No. 5,149,538, discloses inclusion, in a transdermal deliverysystem for opioids, of an encapsulated antagonist as a control on therate of delivery of the opioid.

BRIEF SUMMARY OF THE INVENTION

The drug delivery system of the present invention takes the form of anocclusive patch, which can be applied to a clean section of skin. Theocclusion entraps sweat which in turn serves to hydrate the skin(specifically, the stratum corneum), thus facilitating drug penetrationacross the skin. The entrapped sweat can also saturate a matrix in whicha specific drug is dispersed in microencapsulated form. The matrix isformulated from gums and gelling agents, so that it absorbs severaltimes its own weight in moisture.

Drug release from the microcapsules into the matrix depends on therelative ease with which water from the entrapped sweat is able topenetrate the microcapsules' coat to dissolve drug in the inner core.

This process can be closely controlled by selection of the coatingmaterial for the drug, or by manipulating the constituents of thecoating material. For example, the hydrophilic and hydrophobic elementsof the coating material can be designed to affect the water permeabilityof the coating. Dissolved drug then leaches into the matrix and isdelivered through the skin to exert the desired effect.

The present invention also includes a visible indicator, for example,microencapsulated color change indicator, which can be designed, throughits formulation, to effect a visible change at significant time pointsin the lifetime of the patch. Since the mechanism effecting the visiblechange has a commonality or interrelatedness to that responsible for therelease of drug, the manufacture of the indicator can be tailored torepresent the status of drug release from the microcapsules. Forexample, the release of sufficient drug quantity to exert a therapeuticaction can be associated with one visible change, and the nearexhaustion of drug reserves from the microencapsulated core can beassociated with a second visible change. This second feature, inparticular, can serve as an indication to the user that a replacementpatch should be applied. At present, only drugs intended for a prolongedduration of action (i.e., those requiring a sustained release profile)are administered via the transdermal route. This may be due, in part, tothe inability to define precisely the quantity and extent of transdermaldrug delivery in the short and intermediate terms. The use of indicatorswith transdermal drug delivery systems in accordance with the presentinvention, broadens the utility of drug delivery through the skin byallowing precise accurate indication and evaluation of the process ofdrug release, and thus the subsequent link to the desired therapeuticactivity. This invention, therefore, facilitates exploitation of thetransdermal route, where drugs are to be administered through the skinfor short or intermediate durations of action, or in controlled release.

The above-mentioned visible indicator preferably comprises, for example,a layer of microencapsulated colored material visible through thebacking of the patch.

The indicator may advantageously be designed as a system of multiplecolored indicators, to represent the significant time points in theprocess of drug release from the microcapsules. For example, oneindicator can be engineered to change color when a sufficient quantityof drug, determined to be necessary to initiate therapeutic action, hasbeen released from the microcapsules. In a different embodiment, theindicator can be engineered to change color when the drug reserves inthe microcapsules have been depleted, thus providing an easilyinterpreted visual cue to the useful lifetime of the patch. The designof the indicator makes it a particularly suitable model for the processof drug release, since the mechanism responsible for the drug releaseover time can be engineered to be the same as the release rateresponsible for the indicator's visible change.

The present transdermal drug delivery system may be useful andadvantageous in several settings:

In a preferred embodiment, a system in accordance with this inventioncan be used to deliver drugs such as, for example, quinine derivativesor pyrimethamine, in chemoprophylaxis against malaria. Children, forexample, may prefer transdermal medication to the alternative of regularoral medication, and the effectiveness of transdermal medication is notcompromised by the presence of concomitant illnesses and symptoms suchas vomiting or diarrhea. Moreover, the present system can be engineeredto release an antimalarial drug in a "zero order" fashion so that aconstant, stable blood concentration can be maintained, thus reducingthe likelihood of "breakthrough" infection from fluctuations in bloodantimalarial concentration. The useful lifetime of the patch can readilybe assessed, since the color indicator will change as drug is exhausted.

In another preferred embodiment, the system of this invention can beused to deliver analgesic drugs for example, in peri-operative andpost-operative analgesia. The medical literature has shown that the needfor postoperative pain relief is diminished when analgesics areadministered to patients in the pre- or peri-operative period.Analgesics (for example, members of the class of non-steroidalanti-inflammatory drugs, such as flurbiprofen) may be formulated into atransdermal patch for application immediately prior to simple surgicalor dental procedures. These patches will be left on the patient forcontinuing pain relief after the procedure. Such an application reducesthe need for parenterally or orally administered pain relief.Furthermore, transdermal absorption of the analgesic agent will beunaffected by post operative vomiting, or by the absence of food in thegastrointestinal tract (for example, if the patient should have toundergo a preoperative fast). Further uses could include long-term usefor chronic and sub-chronic painful and inflammatory conditions.

In yet another preferred embodiment, the system of this invention can beused to deliver topical doses of local anesthetic agents prior to minorsurgical procedures or before the insertion of intravenous cannulae.Local anesthesia in this manner may be of particular advantage wheresubcutaneous or intradermal injections are a relative contraindication(for example, where such injections will distort the structure ofunderlying tissue and lead to an increase in scarring). In such asetting, patches can be applied by the patient, a relative or friend, orby a health professional in advance of the procedure. Multiple colorindicators can then be designed to change with significant timelandmarks. For example, one indicator may be used to signify whenadequate quantities of local anesthetic should have been released toeffect pain relief, and another indicator may signify when most of thedose has been delivered from the patch.

In still another preferred embodiment, the system of this invention isuseful where constant levels of an antibiotic drug are desirable toprevent or treat recurrent or persistent infections; for example, forthe delivery of anti-tuberculous drugs where sustained therapy isindicated. A patch containing a drug such as trimethoprim can also bedesigned to deliver effective levels of the drug to prevent therecurrence of urinary tract infections. This principle is alsoapplicable for protecting susceptible patients (for example, those witha history of rheumatic heart disease) from the risk of heart valvedamage from Streptococcus spp. following surgical or dentalinstrumentation. In this setting, a patch containing a suitableantibiotic drug will be applied immediately before the procedure, andthen maintained for an appropriate length of time afterwards, so that aconstant level of the drug will be present during the period of risk.Specific design of the indicator to change color as the drug reservesare depleted should minimize the likelihood of sub-optimal drugdelivery, and result in successful eradication of the pathogenicmicrobes, or prophylaxis therefrom.

In another embodiment, the system can be designed as a reliable means ofdelivering drugs to treat patients with central nervous system deficits,for example the anti-psychotic drugs or medications to manageAlzheimer's disease. The application of a transdermal therapeutic systemis easily supervised by a family member or a care provider who need nothave a healthcare background. The patch does not require the patient toremember special instructions or to undertake complicated procedures fortherapy maintenance, and the color indicators will be useful as a meansto assess patient compliance and to assure dose delivery. (For example,if the patch is removed from the skin for any length of time, theindicator's color change would not be observed at the appointed time,and should prompt further investigation.)

BRIEF DESCRIPTION OF THE DRAWINGS

There are shown in the drawings forms of the inventions which arepresently preferred, although it should be understood that the inventionmay be embodied in other specific forms without departing from itsessential attributes.

FIG. 1 is a schematic side elevation view, in cross-section, showing thestructure of a drug delivery system in accordance with the invention.

FIG. 2 is a graph depicting the rate of drug release versus time for apatch designed for slow and sustained release.

FIG. 3 is a graph depicting the rate of drug release versus time for apatch designed for rapid drug release.

FIG. 4 is a graph depicting the rate of drug release versus time for apatch designed for a combination release characteristic (i.e., initiallyrapid, followed by a sustained release profile).

Referring now to the drawings in detail, there is seen in FIG. 1 atransdermal patch, designated generally by the reference numeral 10. Thepatch 10 comprises a translucent water-impermeable shell, or backinglayer 12. The shell 12 provides a reservoir 14 for the other componentsof the system, described below. In a presently preferred form of theinvention, the shell 12 may be made of a plastic composite, formed byany suitable technique. Other suitable materials, generally of plasticpolymeric composition, may be used for the shell 12, and will occur tothose skilled in the art. The reservoir 14 may be said to have first andsecond faces 14a and 14b, the purpose of which is explained below.

A layer 16 of suitable pressure-sensitive adhesive material, of aconventional type, is disposed around a flange portion 18 of the shell,and enables the flange portion 18 to be secured to the skin of a user ofthe patch 10. It will be understood that when the patch 10 is providedto a user, the adhesive layer 16 will ordinarily be covered by adisposable protective layer, not shown.

When attached to the skin of a user, the shell 12 provides theabove-mentioned occlusive covering, which enhances the hydration of theskin area covered by the patch 10. Hydration of the skin area, as willbe explained, fosters release and absorption of the drug associated withthe patch 10.

Within the reservoir 14 is a matrix, designated generally by thereference numeral 20. The matrix 20 is formulated to absorb severaltimes its own weight in water, and may comprise, for example, guar,acacia or xanthan gum, or a gelling agent or polymer such ascarboxypolymethylene, hydroxyethylcellulose or polyacrylamide. In thecase of guar gum, for example, the matrix 20 can be made to absorbbetween five and ten times its own weight.

Within the matrix 20 in the illustrated form of the invention aremicroencapsulated particles of the drug. The drug microcapsules 22 inthe illustrated embodiment include a core or granule 24 of activeingredient or ingredients (drugs), microencapsulated within a coatingmaterial 26. The sensitivity of the coating material to the permeationof moisture is controlled by the choice of coating material (forexample, acrylate resins, or methylmetacrylic acid co-polymers), or byits formulation (for example, by incorporating different proportions ofhydrophilic ethylcellulose derivatives and hydrophobic methylcellulosederivatives). Coatings 26 are selected or designed to be more or lesssusceptible to moisture penetration and subsequent drug coredissolution, according to the desired drug release characteristics. Itwill be understood that the dissolution of the drug enables it to leachinto the matrix 20 for delivery to, and subsequent passage through, theskin of the user.

It should now be apparent that judicious selection or manipulation ofthe microcapsule coating material 26 allows control of the rate of drugrelease from the core 24. A coating 26 that is relatively impervious tomoisture, for example, one that is thicker or less permeable because ofits physico-chemical properties, or one that contains a higher contentof hydrophobic elements in its composition, will result in a moregradual drug release over a sustained period. FIG. 2 depicts ingraphical form a drug release profile for a patch designed for slow andsustained release. This type of release characteristic may be desiredfor maintaining stable concentrations of drugs for a prolonged duration,for example, in the chemoprophylaxis of malaria. In contrast, a coating26 that is relatively permeable to water will rapidly release the drugover a short period. FIG. 3 depicts in graphical form a drug releaseprofile for a patch designed for such rapid release. This may be thegoal where the patch is intended to deliver a local anesthetic drug,when a rapid onset, and a subsequent rapid discontinuation of thebiological effect is desired. A combination of both releasecharacteristics may be useful in the appropriate setting, for example,in the patch for delivering a drug to effect peri- and post-operativeanalgesia, since the goal here is a rapid onset, followed by a sustainedmaintenance of pain relief. FIG. 4 depicts in graphical form a drugrelease profile for a patch of this type. A combination of both theinitially rapid release followed by a sustained release profile can beachieved by the incorporation of different "populations" ofmicrocapsules into the patch 10. (For example, microcapsules withcoating materials of variable composition and having a variety of waterpermeability characteristics may be included in the formulation toprovide the desired release characteristics).

Also provided within the reservoir 14 adjacent to and operativelyassociated with the face 14b, and visible through the patch backing, isa microencapsulated color indicator designated generally by thereference numeral 28. This indicator may be designed to change color inresponse to the presence of water, electrolyte or other secretion, andmay be manufactured from inorganic salts that will change color withhydration (for example, anyhdrous copper sulfate or cobalt chloride).Alternatively, colorful dyes (like amaranth or mercurochrome) can bemicroencapsulted to effect a color change when released. The utility ofsuch an indicator is that it exploits the common mechanism foractivating both the indicator's color change and the process for drugrelease, namely, the ease with which water, electrolyte or othersecretion penetrates the coating material of the microcapsules.

Commonality or interrelatedness of mechanism enables the color indicatorto be tailored to accurately reflect the status of drug release from themicrocapsules, either by an appropriate choice of coating material or bymanipulation of the components in the coating. This feature isadvantageous in instances where the timing of events such as the onset,peak, and decline of therapeutic effect is an important consideration inthe proper use of the drug. For example, in designing a patch for thedelivery of local anesthetic agent, a series of different colorindicators can be fabricated to change color at time pointscorresponding to the time of onset of local anesthesia, the time of peakeffect, and the time at which the anesthetic effect begins to wear off.The color changes that will indicate these important "landmarks" in thelifetime of the patch will very closely reflect the true status (i.e.,the quantity and extent) of drug release from the drug microcapsules.

The commonality of mechanism as between the indicator and the drugrelease, also allows the color change to indicate that successful drugdelivery has taken place. This feature will be useful in ensuringcompliance to dosing instructions, since the color change will not beachieved without continued contact with the skin. Observation,therefore, that a color change did not occur at the expected time canprompt further investigation. Patches in accordance with this inventionwill have at least one indicator, designed to change color when the drugreserves within the microcapsules are almost exhausted. This feature isintended to prompt the user to discard the old patch and to apply areplacement patch, where required.

The above-described patches 10 may be used in conjunction withpreparatory skin cleanser, containing, for example, alcohol and a weaklybuffered acidic or basic solution. The solvent would serve to removesurface grease to eliminate a barrier to absorption at the skin, and abuffered acidic or basic solution may be selected according to thephysical or chemical properties of the particular drug to beadministered and to maximize drug stability and enhance transdermalpenetration.

This invention includes the description of a microencapsulated colorchange indicator that can be designed, through its formulation, toeffect a visible change at significant time points in the lifetime ofthe patch. Since the dynamics of the mechanism effecting the colorchange are related to that responsible for the release of drug, themanufacture of the color indicator can be tailored to represent thestatus of drug release from the microcapsules. For example, the releaseof sufficient drug quantity to exert a therapeutic action can beassociated with one color change indicator, and the near exhaustion ofdrug reserves from the microencapsulated core can be associated with asecond color change. This second feature, in particular, will serve asan indicator to the user that a replacement patch should be applied.

The present invention may be embodied in other specific forms withoutdeparting from its spirit or essential attributes. Accordingly,reference should be made to the appended claims rather than theforegoing specification, as indicating the scope of the invention.

We claim:
 1. A drug delivery system for the delivery of a drug acrossthe skin of a user comprising:a shell, said shell providing an occlusivecovering on the skin of the user to enhance the hydration of the skin,said shell comprising a reservoir having a first face and a second face,said reservoir having therein a matrix adapted to absorb moisture fromthe skin and hydrate the skin to facilitate penetration of the skin by adrug, said reservoir further having therein a plurality ofmicrocapsules, said microcapsules being dispersed within said matrix andhaving contained therein an effective concentration of a drug and acoating formulated to be susceptible to penetration by moisture; meanson said first face of said reservoir for adhering said shell to theskin; and a visible indicator operatively associated with said secondface of said reservoir, said indicator comprising a reagent formulatedto visibly change in response to the presence of moisture, electrolytesor other secretions in said matrix, said visible indicator comprising afirst indicator and at least a second indicator, said first indicatorproviding a first visible change indicative of a first event in relationto delivery of said drug, and said second indicator providing a secondvisible change indicative of a second event in relation to delivery ofsaid drug.
 2. A delivery system in accordance with claim 1, wherein saidvisible indicator is a color indicator, said indicator comprising aplurality of microparticles permeable to moisture and having containedtherein a chemical intermediate adapted to absorb moisture from saidmatrix and to irreversibly change color in response to the moisturelevel in said matrix.
 3. A delivery system in accordance with claim 2,wherein said microscapsules are uniformly dispersed within said matrix.4. A delivery system in accordance with claim 2 wherein said drugcontaining-microcapsules are so constructed as to control the rate ofrelease of said drug into said matrix.
 5. A delivery system inaccordance with claim 4, wherein said chemical intermediatecontaining-microparticles are so constructed as to control the rate ofabsorption of said moisture.
 6. A delivery system in accordance withclaim 5, wherein said color change is indicative of the release of saiddrug from said microcapsules and the depletion of said drug from saidmicrocapsules.
 7. A delivery system in accordance with claim 6, whereinsaid color change is indicative of the lifetime of said system.
 8. Adelivery system in accordance with claim 7, wherein said matrix isadapted to absorb moisture from the skin several times the weight ofsaid matrix.
 9. A delivery system in accordance with claim 8, whereinsaid matrix is selected from the group consisting of guar, acacia,xantham gums.
 10. A delivery system in accordance with claim 8, whereinsaid matrix is selected from the group consisting of a gelling agentselected from the group consisting of carboxypolymethylene,hydroxyethylcellulose and polyacrylamide.
 11. A delivery system inaccordance with claim 8, wherein said drug is adapted for thechemoprophylaxis of malaria.
 12. A delivery system in accordance withclaim 8, wherein said drug comprises an analgesic for use inperi-operative and post-operative pain relief.
 13. A delivery system inaccordance with claim 8, wherein said system is adapted for the topicaldelivery of anesthetic agents.
 14. A delivery system in accordance withclaim 8, wherein said drug comprises an antibiotic agent.
 15. A deliverysystem in accordance with claim 8, wherein said drug comprisesmedication for treating the central nervous system deficits.
 16. Adelivery system in accordance with claim 1, wherein said visibleindicator comprises a first indicator and a series of subsequentindicators, said first indicator providing a first visible changeindicative of a first event in relation to delivery of said drug, andeach subsequent indicator providing a visible change indicative of arespective subsequent event in relation to delivery of said drug.